Cellular Shifts

Ingested K⁺ is absorbed rapidly and enters the portal circulation, where it stimulates insulin secretion. Insulin increases Na⁺,K⁺-ATPase activity and facilitates potassium entry into cells, thereby averting hyperkalemia. β₂-Adrenergic stimulation also promotes entry of K⁺ into cells through increased cyclic adenosine monophosphate (cAMP) activation of Na⁺,K⁺-ATPase.

Renal Handling

An increase in extracellular potassium concentration also stimulates aldosterone secretion (via angiotensin II), and aldosterone increases K⁺ excretion. In the steady state, K⁺ excretion matches intake, and approximately 90% is excreted by the kidneys and 10% in the stool. Renal K⁺ excretion is mediated by aldosterone and sodium (Na⁺) delivery (glomerular filtration rate [GFR]) in principal cells of the collecting ducts.³ K⁺ is freely filtered by the glomerulus, and almost all the filtered K⁺ is reabsorbed in the proximal tubule and loop of Henle (Fig. 1). This absorption in the proximal part of the nephron passively follows that of Na⁺ and water, whereas reabsorption in the thick ascending limb of the loop of Henle is mediated by the Na⁺,K⁺,2Cl⁻ carrier (NKCC2) in the luminal membrane. K⁺ is secreted by the connecting segment, the principal cells (see Fig. 1) in the cortical and outer medullary collecting tubule, and the papillary (or inner medullary) collecting duct via luminal potassium channels (ROMK). Secretion in these segments varies according to physiologic requirements, and is responsible for most of the urinary potassium excretion. Secretion in the distal segments is also balanced by K⁺ reabsorption through the intercalated cells (see Fig. 1) in the cortical and outer medullary collecting tubules. This process is mediated by an active H⁺,K⁺-ATPase pump in the luminal membrane and results in both proton secretion and K⁺ reabsorption. The kidneys are better at increasing K⁺ excretion than decreasing excretion. As a result, K⁺ depletion and hypokalemia can occur from inadequate intake. Hyperkalemia usually occurs when renal excretion is impaired (GFR <20 mL/min).

Figure 1 Renal handling of potassium.

Almost all of the filtered K is reabsorbed in the proximal tubule and the loop of Henle. Black arrows represent percent of potassium reabsorbed at proximal tubule (thick ascending limb and medullary). Dashed arrows represent sites of potassium secretion in the cortical collecting duct (CCD) and medullary collecting duct.

Definition

Hypokalemia is defined as a serum potassium concentration below 3.5 mmol/L. Hypokalemia can be further arbitrarily graded by severity.

Relative severity is defined as:

Moderate severity is defined as:

Severe hypokalemia is defined as:

Prevalence

Hypokalemia is found in about 20% of hospitalized patients, but it occurs in less than 1% of otherwise healthy adults.

Pathophysiology

Hypokalemia can result from transcellular shifts (from extracellular into intracellular spaces), or when potassium losses are increased; these losses can be from renal or nonrenal causes (Box 1). Transcellular shifts can occur in pathologic conditions associated with a catecholamine surge, such as chest pain syndromes, or mediated by acid-base disturbances. Loop or thiazide diuretic use, aldosteronism, or other renal diseases (e.g., postobstructive diuresis, cortical necrosis) can cause excessive renal potassium losses. The renal and nonrenal causes of K⁺ loss can be determined by laboratory tests (Fig. 2).

Figure 2 Hypokalemia-diagnostic algorithm.

Clinical Effects

Normal individuals with hypokalemia are usually asymptomatic. Manifestations of hypokalemia include generalized muscle weakness, ileus, and cardiac arrhythmias. In patients with ischemic or scarred myocardium, left ventricular hypertrophy, congestive heart failure, or myocardial infarction, hypokalemia is associated with an increased incidence of ventricular ectopy, ventricular tachycardia, and ventricular fibrillation. In those patients with heart disease at risk for serious ventricular tachyarrhythmias, even relative hypokalemia ([K⁺] = 3.5 to 4.0 mmol/L) may require potassium supplementation to prevent development of overt hypokalemia. More severe hypokalemia (<2.5 mmol/L) can cause myopathy that can progress to rhabdomyolysis, and ascending paralysis with respiratory arrest (<2.0 mmol/L; see Box 1).

Diagnostic Workup

When hypokalemia is reported, the initial step is to ascertain whether it is associated with clinical symptoms or arrhythmias that would require prompt intervention. In the absence of compelling indications for immediate therapy, a careful history and physical examination should be performed. Important clinical clues such as medication, vomiting, and hypertension should be specifically sought. Factitious or spurious hypokalemia, which can occur in patients with leukemia or elevated white cell counts because K⁺ is taken up by these metabolically active cells in the test tube, should be ruled out. If true hypokalemia is present, then determine whether it was caused by a transcellular shift or a decrease in total body potassium. Hypokalemia from transcellular shift is managed by treating the underlying condition or removing the offending agent. Decreased total body K⁺ require further diagnostic workup. Urine potassium, chloride, creatinine, and serum aldosterone levels are determined to distinguish the causes of extrarenal and renal losses of K⁺ so that the primary condition can be treated, in addition to replacement therapy (see Fig. 2).

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